Retroviruses lead to chronic infection in mammals. Retroviruses are packets of infectious nucleic acids (i.e. genetic material) surrounded by a protective protein coat. Retroviruses are incapable of generating metabolic energy or synthesizing proteins, and thus are characterized by dependence on living cells for replication and proliferation. A retrovirus contains three enzymes: (1) reverse transcriptase, (2) protease, and (3) integrase. Current antiviral drug therapy focuses on the inhibition of reverse transcriptase and protease enzymes.
HIV is a prototypic retrovirus that causes the acquired immunodeficiency syndrome [AIDS] in humans and related primates. Worldwide, AIDS has claimed over 11 million lives. HIV currently infects more than 30 million people. Since the first reported cases of AIDS almost 20 years ago, the medical community has learned much about this retroviral disease and its diverse manifestations. A number of clinical manifestations of HIV infection, however, remain unexplained despite the efforts of the medical community to discover their etiology.
The Center for Disease Control and Prevention (the “CDC”) has developed a “case definition” of the specific findings which, if present in a person with HIV, define AIDS. See Center for Disease Control and Prevention, 1993 Revised Classification System for HIV Infection and Expanded Surveillance Case Definition for AIDS Among Adolescents and Adults, MMWR Morb Mortal Wkly Rep, 41(RR-17): 1–19(1992). The CDC's case definition falls into three broad categories: (1) CD4 immune cell depletion, (2) opportunistic infections, and (3) malignancies.
In addition to the case definition of AIDS, a number of metabolic changes are associated with this chronic infection. Among them are alterations in the circulating concentrations of amino acids. Amino acids are often referred to as the building blocks of proteins. Of the common amino acids, ten amino acids are “essential.” The essential amino acids are those which the body cannot synthesize and therefore must be obtained directly through the diet.
Tryptophan, an essential amino acid, is known to be depleted during HIV infection. The body utilizes dietary-derived tryptophan for several important biochemical functions, including: (1) as a building block in the synthesis of proteins, (2) as a precursor of niacin and nicotinamide adenine dinucleotide [NAD], and (3) as a precursor of serotonin. Attempting to simply replete plasma tryptophan directly through pharmacologic doses of tryptophan is not advisable given the history of patients developing “eosinophillia myalgia syndrome.”
Chronic retroviral infections lead to an ongoing metabolic burden on the infected subject. This burden in HIV infection includes: (1) the turnover of CD4 cells, (2) the disturbance of lipid metabolism, (3) the depletion of serotonin, (4) the depletion of plasma tryptophan [as discussed above], and (5) the depletion of intracellular NAD. The infection, over the course of months, leads to immunodeficiency (marked by CD4 depletion) and opportunistic infections. The infection also leads to a metabolic disease state marked by a number of other manifestations, including a non-specific “wasting syndrome” and the specific disturbances and depletions previously mentioned in this paragraph.
Presently, no cure exists for HIV infection. Current treatments for HIV infected patients tend to focus on agents which inhibit two viral enzymes: the HIV-reverse transcriptase [reverse transcriptase inhibitors] or the HIV-protease [protease inhibitors]. Such agents include among others, ZDV (zidovudine), DDI (2′–3′-dideoxyinosine), and DDC (2′–3′-dideoxycytidine), each of which blocks the HIV proliferation in cells (ZDV, DDI, DDC and other such agents are referred to as the “licensed antivirals”). Unfortunately, the inhibition which occurs with the licensed antivirals is incomplete. Over time, HIV becomes resistant to the licensed antivirals. This resistance can result in a resumption of progressive immune system destruction.
Zidovudine, a licensed antiviral compound, is the only compound known to replete plasma tryptophan in HIV infected persons. However, zidovudine which is a reverse transcriptase inhibitor, causes a number of side effects including headache, nausea, and bone marrow suppression. Furthermore, HIV can develop resistance to Zidovudine, an event which would be expected to result in recurrent tryptophan depletion.
Since HIV depletes plasma tryptophan and since this essential amino acid is required in a range of biologically necessary tasks, replenishing plasma tryptophan is essential in maintaining overall health in the HIV infected state. Although the antiviral drug zidovudine leads to an increase in plasma tryptophan in HIV infected persons, this reversal would be expected to last only so long as virus inhibition persists, and antiviral drug failure is expected with time given the incomplete nature of the drug's inhibitory effect. Niacin, as an agent to reverse infection-induced metabolic changes, works on the host side of the virus-host interaction and therefore would not be subject to the same risk of eventual viral drug resistance.